Method for modulation of neuronal activity in the brain by means of sensory stimulation and detection of brain activity

ABSTRACT

The invention relates to a method for controlled modulation of physiological and pathological neuronal rhythmic activity in the brain by means of sensory stimulation, which is capable of diagnostically ascertaining functional disorders in the brain and of alleviating or eliminating the symptoms of a functional disruption. According to the invention, the method comprises generating a plurality of pulses at a plurality of excitation frequencies, respectively, to stimulate neuronal rhythmic activity in a patient&#39;s brain; measuring the neuronal rhythmic activity in response to the pulses; determining an excitation frequency in which the measured neuronal rhythmic activity has a maximum amplitude of pathological rhythm; generating an entraining periodic pulse sequence operating at the excitation frequency; and generating a desynchronization pulse following the entraining periodic pulse sequence to desynchronize the neuronal rhythmic activity, where the pulse are either visual or acoustic or tactile.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 10/522,933, filed Jan. 24, 2005, which is the US national phase ofPCT application PCT/DE2003/002250, filed 5 Jul. 2003, published 26 Feb.2004 as WO 2004/016165, and claiming the priority of German patentapplication 10233960.0 itself filed 29 Jul. 2002, the entire contents ofeach of which are incorporated by reference.

FIELD OF THE INVENTION

The invention relates to a device for the need-controlled modulation ofphysiological and pathological neuronal rhythmic activity in the brainby means of sensory stimulation.

BACKGROUND OF THE INVENTION

To diagnose the excitation processes of the brain, typically stimulationtechniques like continuous excitation, multiple single excitations andperiodic excitations or stimulations have been used. For continuousstimulation, for example, continuous sound or visual patterns areconsidered. Individual excitations result for example in so-calledacoustic or visually evoked potentials. As periodic excitation, astimulation with flickering light can be used, for example, to diagnosea photosensitive epilepsy. Based for example on excitation responses ofthe brain or the sense organs as measured by means of electrodes and thepsychophysical findings (for example the number of recognized patternsor heard sounds) conclusions can be drawn as to the functioning of thesensory system explored.

In biofeedback training, optical or acoustic feedback effects aretherapeutically used to bring about in the patient a voluntary controlof some action of the patient's bodily function, especially thesympathetic nervous system, in a desired manner. The feedback signalsenable, therefore, a self-control and increase the influence upon thebodily function which pertains by the patient. Applications ofbiofeedback training for example include applications in functionalheart conditions and neuromuscular stress states. With previousdiagnostic methods, the dependency between excitation responses and theparticular activity were not explored in detail. Only a relatively fewparameters of cerebral activity were investigated. With the standardprocess it is not possible to match the stimulation to the specificrhythmic brain activity of individual patients so as to be able todetect significantly more functional and response ranges. It isespecially not possible to investigate the effect of targetedmanipulations in rhythmic cerebral brain activity in different frequencyregions (for example their amplitude damping) and different brain areason information processing.

It is a prerequisite of biofeedback training that the patientvoluntarily and willingly desires the improved bodily function andparticipates therein. With most of the organ systems of the body and formany brain functions this is not the case however or is not the case toa sufficient degree. Difficulties are encountered when the patient has acerebral disorder, for example, is a neglected patient following a braininfarct or has some other illness or medical condition following anillness which interferes with understanding or recognition and whichdisables a voluntary effect even on simple bodily functions, makes themmore difficult or even impossible. Thus neglect patients whose bodyparts no longer respond can be scarcely responsive to biofeedbacktraining at least with respect to the body parts which arenonresponsive.

OBJECT OF THE INVENTION

It is thus an object of the invention to provide a device which enablesthe need-directed modulation of the physiological or pathologicalneuronal rhythmic activity of the brain. The device should be able toreliably and suitably diagnose functional disturbances of the brain andto ameliorate or eliminate the symptoms. In addition the device shouldenable brain activity, which is relevant for sensory informationprocesses to be investigated and manipulated for diagnostic andtherapeutic purposes. In addition the device should so operate that withmany patients in which the illness may have resulted in at least onebodily function to be no longer capable of voluntary influence, thecontrol of that bodily function to be improved or restored.

OBJECT OF THE INVENTION

Starting from a device for need-controlled modulation of physiologicaland/or pathological neuronal rhythmic activity, these objects areattained with a control unit, a stimulator, and at least one means fordetecting brain activity connected with the control unit.

With the features of the invention it is possible directly to modulatein an as-required manner the physiological or pathological neuronalrhythmic activity of the brain so that it comes close to its naturalfunction or is identical therewith.

The device is suitable for reliably diagnosing functional disturbancesof the brain and symptomatically ameliorating them or eliminating them.The device enables a new diagnostic method to be carried out in which,matched to the existing or present rhythmic brain activity of a patient,a targeted manipulation of the rhythmic activity is possible indifferent brain regions. In this manner the neuronal informationprocessing can be diagnostically and therapeutically explored andmodulated. Furthermore, the device of the invention operates in suchmanner that the problem that many patients have many bodily functionswhich cannot be voluntarily influenced, can be overcome.

BRIEF DESCRIPTION OF THE DRAWING

The drawing shows an exemplary configuration of the device according tothe invention in block diagram form for patients as well as severalpulse sequences involved in the diagnosis and treatment. In the drawing:

FIG. 1 is a block diagram of the device.

FIG. 2 is a stimulus sequence for excitation at the resonant frequencyat which, for the purpose of desynchronization, a single pulse isapplied in the vulnerable phase.

FIG. 3 a illustrates an example of the course of the pattern over timeof the sensorial excitation produced by means for generating thesensorial excitations 1.

FIG. 3 b illustrates a schematic illustration of the activity pattern ofthe brain region having the disorder and associated with theillustration in FIG. 3 a.

FIG. 4 a illustrates a scan of the excitation frequency with which thefrequency of the pulse sequence slowly varies.

FIG. 4 b illustrates a rise of the natural rhythmic activity.

FIGS. 5 a-f illustrate schematic illustrations of the resetting curvesof a phase associated with a-standardization process.

FIG. 6 is a flow diagram for the mode of operation according to theinvention of the device.

SPECIFIC DESCRIPTION

FIG. 1 shows a device with a stimulator 1 (1 a, 1 b) in front of which apatient is seated. On the head of the patient a sensor 2 is applied, thesensor 2 being connected by an isolating amplifier 3 to a control unit4. The device comprises a receiver 5, which also is connected to thecontrol unit 4 and which can register the reactions of the patient. Inaddition, the device encompasses a means for monitoring the stimulation6 which is applied over a means for data processing and for displayingthe data so that the results can be visually and/or auditoriallydelivered to the investigator. The control unit 4 is connected with themeans 6 for monitoring the stimulation. The sensor 2, the receiver 5,the stimulator 1 and the means 6 for monitoring the stimulation can alsobe in a contact-free connection with the control unit 4, for examplethrough transmitters and receivers.

FIG. 2 shows a schematic pattern of a pulse sequence for a repetitiveapplication. This pulse sequence has a periodic succession of pulses andis followed by a desynchronization pulse (last pulse). The frequency ofthe periodic pulse sequence is the resonance frequency of the rhythm tobe desynchronized. The purpose of the pulse sequence is to effect anentrainment which controls the phase dynamic of the rhythm to bedesynchronized. After a constant time interval, the desynchronizationpulse is applied in the vulnerable phase of the neutral rhythm. Theabscissa is a time axis in any optionally selected unit while theordinate gives an intensity of the excitation also in any selected unit.

FIG. 3 a again has an abscissa formed by a time axis in any chosen unitsand an ordinate which gives an intensity of the excitation also inselective units. The time segments T₁ and T₂ as well as T₄ and T₅correspond to the configuration in FIG. 2. In the time segment T₃, aperiodic excitation sequence is supplied whose frequency differs fromthe resonance frequency of the neural population to be desynchronized.In the time segments T₁ and T₂ as well as T₄ and T₅, the desynchronizingstimulation illustrated in FIG. 2 are respectively carried out.

In FIG. 3 b, the abscissa has a time axis which has the same time unitsas in FIG. 3 a. The ordinate indicates schematically the amplitude as afunction of time in a sliding time window of the rhythm to bedesynchronized in optional units. The time segments T′_(k) are identicalwith the time segments T_(k), whereby k=1, 2, 3, 4, 5. During theentrainment in time segment T₁, apart from a control of the phasedynamic there is additionally a resonance-like amplification of theamplitude. The desynchronizing individual excitation in the time segmentT′₂ encounters the neuronal rhythm in its vulnerable phase anddesynchronizes it so that at the end of this stimulation the amplitudeis minimal. In time segment T₃ there is further sensor stimulus so thatthe patient can accomplish his goals, for example, the detection ofspecial patterns in an on-going manner. To maintain the suppression ofthe pathological rhythm as long a possible, in the time segment T′₃, anexcitation is periodically applied at a frequency different from theresonant frequency. As soon as the amplitude of the desynchronizedrhythm again exceeds a threshold value, the desynchronization step iscarried out anew so that the stimulation in the time segments T′ and T′₅is identical with the stimulation in the time segments T′₁ and T′₂.

In FIG. 4 a the abscissa is the time axis in arbitrary units and theordinate gives the intensity of the stimulation also in arbitrary units.FIG. 4 a shows schematically the stimulation used for the frequencyscan. In this case a periodic excitation sequence is applied whosefrequency varies slowly and in this example slowly increases.

In FIG. 4 b, the abscissa is the same time axis with the same units asin FIG. 4 a. The ordinate indicates schematically in a sliding timewindow the amplitude obtained with time of the rhythm to bedesynchronized, also in arbitrarily chosen units. Corresponding to theexcitation frequency which is illustrated by the pulse sequence shown inFIG. 4 a, a resonance frequency is produced, i.e. a resonance isgenerated in which the amplitude of the neuronal rhythm increases. FIG.5 illustrates phase resetting curves in which φ_(e) over φ_(b) isillustrated. φ_(e) is the phase of the neuronal activity determineddirectly following stimulation or at a constant time delay afterstimulation. φ_(b) is the phase of the neuronal activity determinedeither directly at the point in time at which the stimulation commencesor at a constant time interval prior to the commencement of stimulation.The phases φ_(e) and φ_(b) are given in radians. Each partial Figurea)-f) corresponds to a series of test excitations with the samestimulus, that is an excitation with constant intensity and excitationduration, applied with different values of the starting phase φ_(b). Theeffect of the excitation on the phase dynamics for the neuronal rhythmto be desynchronized was evaluated by means of the phase resettingcurves. In the partial Figures a) to c), the mean gradient of the curvewas equal to 1, while in partial Figures d) to f), the mean gradient ofthe phase resetting curves were equal to zero. By a “mean gradient” thegradient obtained over a period of φ_(b) is meant. The transitionbetween a phase resetting curve with a mean gradient 1 to a phaseresetting curve with a mean gradient equal to zero is found betweenpartial FIGS. c and d in the region of the vertical arrow with respectto the previously elevated phase φ_(b). This value of the phase φ_(b) isthe vulnerable phase of the neuronal rhythm to be desynchronized. Theoptimum value for the intensity lies between the two intensity values ofpartial Figures c) and d). To obtain this value one can either selectvariations approximating the intensities of c) and d) or preciselygenerating still further phase resetting curves with intensity valuesbetween those of c) and d).

Initially there is a determination of the frequency spectrum underspontaneous conditions (1), that is without stimulation, whereby thepatient is destressed and for example has his or her eyes open for 5minutes and the eyes closed over a further period of 5 minutes. Withopen or closed eyes, respective brain rhythms which are especiallystrong or especially weak are obtained. For example the α rhythm istypically more strongly expressed with closed eyes and more weaklyexpressed by contrast with open eyes. A strong expression of a neuronalrhythm means that this rhythm especially has a large amplitude. In thismanner the point width of the expression of the physiological orpathological rhythms which arise without stimulation can be determined.

Next a frequency scan is carried out (evaluation of the strength of theresonance by means of an amplitude determination of the excited rhythm),possibly together with determination of the quality of the entrainmentover determination of the strength of the phase synchronization betweenthe excitation sequence and the excited rhythm.

Depending upon the results from (1) and (2), either of two differentprocesses develop. In case the patient's natural and nonpathologicalrhythmic activity is too weakly expressed or is mainly not present, aneed-controlled synchronization is carried out in steps (3-5). In casethe patent has a pathological rhythmic activity, a need-controlleddesynchronization is carried out in steps (6-9).

The need-controlled synchronization (3) can be carried out in turn intwo ways: in the context of a simple control function, at the beginningof a sensory stimulation the excitation frequency /_(A) and theintensity are established and maintained constant during the stimulation(4). In a preferred embodiment of the invention the stimulation iscommenced by values suitable for step (2) of the excitation frequency/_(A) and the intensity (5). The control unit 4 matches however in thismode the parameters (especially the intensity) as controlled by need.

For the need-controlled desynchronization, initially the quality of theentrainment evaluated (6) and then a determination is made of thevulnerable phase (7), which—as described below—is associated with adetermination of the optimum excitation intensity or excitationduration. The need-controlled desynchronization can then be effected intwo ways: either a repetitive application of the sensory stimuli (8) iscarried out or a restraining application is carried out (9). Duringrepetitive application (8), the same desynchronizing excitation sequenceis repetitively supplied whereas in the pauses therebetween noexcitation is effected. During the continuous application (9) bycontrast, sensory stimuli are continuously applied and upon exceedingthe threshold of the neuronal activity to be desynchronized, the samedesynchronizing excitation sequence is always applied.

In practically all of the steps, through the means for visualization(FIGS. 1 and 6) a feedback to the investigator can and should beprovided.

Below the components of the device according to the invention aredescribed in detail and their functions explained.

The stimulator 1 is an excitation pulse generator which produces signalswhich can be consciously or unconsciously perceptible to the patient.Basically in this manner all signals which can be sensorially processedby patients can be generated. For example, visual excitation signals,acoustic excitation signals or signals which excite the sense of tasteor, less probably, signals which evoke the pain sense can be mentioned.Visual excitations can include images or patterns. The visualexcitations can be outputted, for example, through a special displayscreen 1 a or spectacles or glasses provided with shutters 1 b. Thedisplay screen can for example be a projection screen which through ashutter diaphragm with a projector which displays a continuous imageover time, provides the sensory response. The light-blocking mechanismfor the shutter glasses or spectacles and the shutter for the projectorscreen can operate preferably either in accordance with the LCDtechnique or FLC (ferroelectric liquid crystal) technique. The imagesand patterns which are used to evoke the visual responses can be thoseknown to the artisan. They can be, for example, Kanisza figures.

All tones or complex noises or sounds can be used as acoustic stimuli,like for example iterations of time-delayed broad band noise or soundsin the audible frequency range which can be outputted by a loudspeaker 1c or head phones 1 d. An excitation stimulator which can excite thesounds of taste or pain sensitivity can for example be a somatosensoricstimulation generator 1 e or a time-modulated laser 1 f. An excitationgenerator in the sense of the invention is thus a device for producing avisual, acoustic or another sensory signal or stimulus. The stimulator 1can output the signals described in a time-based pattern eitherrhythmically or arrythmically. This means that visual images or patternscan be produced in a periodic sequence in time-spaced intervals ofpreferably 1 to 100 Hz or 1 to 70 Hz and/or in complex nonperiodictime-based sequences although the application is not limited to thesefrequencies. Furthermore the intensities or amplitudes of the signalscan also be varied. With visual excitations, not only can the brightnessbe varied but the contrast can be varied as well. Analogously tones canbe applied in a periodic time-based sequence of preferably 1 to 100 Hzand/or in complex nonperiodic time-based sequences. In addition, thesound amplitude can be varied. Analogously the same applies for themeans for generating the other sensory stimuli in which pressure andfrequency can be varied. The complex nonperiodic time-based sequence ofindividual sensory excitations can, as described below, derive forexample from a combination of a periodic excitation sequence withsubsequent qualitatively individual excitations.

In health there is typically rhythmic activity in certain frequencybands and which arises in certain brain areas, for example one canobserve so-called a rhythm (ca. 10 Hz) preferentially in the region ofthe visual cortex. In patients, these physiological rhythms on the onehand may be less expressed or pronounced or on the other hand may havepathological rhythms present in them and which are characterized byatypical, meaning nonphysiological frequency bands. A pathologicalrhythm can also be characterized by a normal frequency content butnontypical anatomical localization. A pathological rhythm need not onlybe limited to a single brain region but can also affect otheranatomically connected brain regions by feeding the pathologicallyrhythmic activity thereto and affecting their functions.

The frequency content of the brain activity of the patient has beencharacterized by the investigator, physiological rhythms which areinsufficiently distinct can be excited or excessively pronouncedpathological rhythms can be suppressed or weakened. If pathologicalrhythms are weakly expressed or pronounced, predominantly periodicstimuli, which are outputted by the stimulator 1, can excite theserhythms. In a further step, through stimuli a desynchronization of thepathological rhythmic activity can be effected. Then the signalsequences which are to effect the desynchronization can differ fromthose which enable the analysis or diagnosis in that these may tend toincrease the pathological rhythmic activity. For desynchronization atleast one desynchronizing pulse is produced.

The signals which are outputted by the stimulator 1 modulate rhythmicactivity in certain brain areas in a manner which can be detected by thesensor 2. The sensor 2 is in this sense a means for detecting brainactivity. As examples of them, scalp-EEG electrodes are MEG sensors,that is SQUIDS, can be mentioned. The apparatus is equipped according tothe invention with at least one sensor which is connected with thecontrol unit 4.

The control unit 4 processes the signal obtained from the sensor 2. Thecontrol unit 4 operates through means for carrying out the processedsteps which have been described in the application. This means can beespecially a computer or an electronic circuit together with a computerprogrammer a programmable processor like, for example, a FPGA (fieldprogrammable array) which is capable of carrying out the steps accordingto the invention of signal collection and evaluation and can control thestimulator 1 in the manner required by the invention.

It is especially advantageous to be able to practice the method withsuitable processors. The term “processor” should not however beunderstood to be limited in any sense. It can be for example anyoptional unit suitable for carrying out computations. It is possible forthe processor to comprise a multiplicity of individual processors whichare advantageously assembled into an appropriate processor unit.

In the sense of the present invention, in addition, any circuitrysuitable for computation can be used. Advantageously, the circuit can bebuilt into a computer or incorporated in a logic component. The means ofthe description for carrying out the method steps of the invention arecomponents of the control unit 4 encompassing at least one componentfrom the group comprised of a computer, an electronic circuit, acomputer program or a processor. The means for controlling the differentmethod steps need not however be provided in a single device.

The control unit 4 determines the degree of expression or development ofa pathological rhythmic activity. If the pathological activity is notpresent or is present only minimally, the control unit 4 providescontrol signals to the stimulator which can then output either nostimuli or other stimuli which differ either in frequency or amplitudeor in frequency and amplitude from prior stimuli. In a diagnosticapplication the frequency and/or amplitude of the stimuli are varieduntil the pathological reaction is a maximum, that means that therhythmic reaction of the pathological brain area is the strongest. Thishas the advantage that otherwise possibly imperceptible pathologicalrhythms can be recognized under certain conditions in case at the pointin time of the diagnostic investigation they might otherwise be tooweak. In this case the control unit operates through means capable ofcalling up a maximum physiological and/or pathological brain activity.This means operating for example through an electronic circuit, aprocessor or a computer and associated software, ensures thatstimulation sequences are provided as described below. The pathologicalrhythmic activity pattern is analyzed by the control unit 4. The controlunit 4 is adapted to provide another time-based pattern of the stimuluswhich is targeted to modulate the pathological activity and especiallyto suppress the pathological activity pattern or to attenuate it. Thus,opposite to the first effect, namely the promotion of the pathologicalactivity, damping and, especially preferably, a complete suppression ofthe pathological brain activity is effected. The sensor 2 continues todetect the brain activity and with the control unit 4 analyzes the newstate of the brain. Through a number of cycles of this type the controlunit 4 is able to determine the stimuli with which the pathologicalconditions can be suppressed as completely as possible.

The receiver 5, which serves for patient control is connected with thecontrol unit 4. The receiver 5, in the sense of the invention can be forexample a push button or a switch or lever which is actuated by thepatient. The patient is instructed to actuate the receiver 5 in responseto certain signals. In this manner the ability of the patient toperceive the sensory stimuli or the treatment effect and the reaction tothe procedure can be controlled. The signals from receiver 5 arecomputed or processed in the control unit 4 and are transmitted to themeans 6 for monitoring the stimulation. Through these means 6 theinvestigator can determine the quality of the stimulation and the resultof its application to the patient. The device according to the inventionequipped with the receiver 5 and the means 6 for monitoring stimulationconstitutes thus a preferred embodiment of the invention.

In the application of the apparatus, two cases A and B can bedistinguished and are explained below by way of example.

A: For patients who naturally have nonpathological rhythmic activitywhich is expressed too weakly or primarily or is usually not present.

B: The patient presents with a pathological rhythmic activity in atleast one region of the brain.

In cases A and B, the control unit 4 operates in the following manner:

Frequency Scan

The frequency scan both in case A and in case B is carried outinitially. In the frequency scan, a periodic sensory stimulation with anexcitation frequency /_(A) is carried out in which /_(A) varies slowlybetween preferably 1 and 100 Hz, especially preferably between 1 to 60Hz. In FIG. 4 a this has been reproduced by way of example with anincreasing frequency of the applied signal sequence. Sensor 2 measuresthe neuronal activity and supplies it to the control unit 4 whichdetermines in which frequency range the neuronal activity develops anexcitation. This excitation can the be quantified by

(i) integrating the amplitude of the power spectrum over the excitedfrequency range or, analogously thereto

(ii) determining the instantaneous amplitude of the frequency range bymeans of the Hilbert transformation.

The device of the invention thus comprises means for carrying out afrequency scan as well as means for carrying out the step (i) and/or(ii).

The electronic circuitry used for example for this purpose or equivalentmeans in control unit 4, as well as a computer program, which forexample operates in accordance with the methods (i) and (ii) can serveas the means for quantifying the neuronal activity.

This frequency scan can be carried out by the control 4 which activatesthe means for generating sensor stimuli 1 so that the respectivefrequency is reproduced in the patient in the form of a sensorystimulus. For this purpose the control unit 4 can act through means forcontrolling the stimulator 2, for example a TTL pulse generator. Thecontrol unit 4 recognizes the signals captured by the sensor 2 or theiramplitudes in the investigative frequency range at which the excitationfrequency produces a maximum excitation. The device thus comprisesadvantageously such means which is capable of investigating in thesignals measured by the sensor 2 apart form the frequency range of theexcitation frequency also other frequency ranges. This means can carryout time-dependent frequency analysis based upon Fourier transformationor wavelet analysis. For this purpose the control unit 4 comprises ameans which is suitable for carrying out these steps. Such means can beas has been described above by say of example, a computer, an electroniccircuit, a processor, a programmable electronic circuit (FPGA) or acomputer program. The frequency of the excited activity can thuscoincide with the excitation frequency or can also not coincidetherewith. Surprisingly it has been found that the frequency of theperiodic stimulus sequence which serves for entrainment follows the lawgiven below:f/ _(R) /f _(A) =n/m  Formula 1where f_(A)=the excitation frequency, that is the frequency of theperiodic stimulus sequence serving for excitation

f_(R)=the frequency of the excited neuronal activity (resonancefrequency)

whereby n and m are small whole numbers, that means≦10, (namely 1, 2, 3,4, 5, 6, 7, 8, 9, 10) for example, n/m=1/1, 1/2, 2/3 etc.

With the aid of the frequency scan, two aspects of the excitationproperties are explored.

1. A determination is made as to whether an excitation will bring abouta physiological rhythm in a frequency range expected for this rhythm.With flicker light stimulation, these frequency ranges can be forexample in the region of 10 Hz, 20 Hz, 40 Hz and 80 Hz. In this case adetermination is made whether a physiological rhythm, which may be ofpathological origin or can develop spontaneously, that is withoutstimulation, is too weakly expressed, can be excited by periodicstimulation.

2. A determination is made as to whether an excitation will lead to apathological rhythm. The latter is characterized by a physiologicalresponse that does not lie in a physiological frequency range or is in aphysiological frequency range but arises at an untypical brain region.The physiological frequency ranges are the frequency ranges at whichneuronal rhythms naturally occur. For example, the α rhythm in theregion of about 10 Hz and β rhythm in the region of about 20 Hz can bementioned. In this manner a determination is made as to whether apathologically generated rhythm can be produced by a periodicstimulation. Such pathological rhythm is typically, although notnecessarily already present under spontaneous conditions, that iswithout stimulation.

After the frequency scan is carried out as described above, theapplication of the invention is effected in accordance with cases A andB below.

A. Need-Controlled Synchronization:

The goal of the need-controlled synchronization is, with patients whohave one or more too weakly expressed physiological rhythms to excitethat by sensor stimuli during treatment. For this purpose the stimulustreatment which is found to be required because of the weakenedphysiological rhythm is improved or enabled. For this purpose the sensor2 registers the neuronal activity of the brain area to be excited. Thesignals measured by the sensor 2 are advantageously supplied to thecontrol unit 4 through an isolating amplifier 3. The control unit 4 canthen control the sensor stimulation in two different ways:

1.) In the framework of a simple control function, at the beginning ofthe sensory stimulation the sensory stimuli or pulses are applied withan excitation frequency f_(A) and the intensity according to the resultsof the frequency scan. These stimulation parameters remain constantduring the sensory excitation.

2.) As under (1), the excitation is commenced with an excitationfrequency f_(A) and the intensities which are appropriate from theresults of the frequency scan. The control unit 4 matches theseparameters during the sensory excitation under need control. That meansthat the control unit 4 reacts to a decrease in the amplitude of therhythm to be excited with an increase in the intensity of the excitingstimulus. In this case the control unit 4 acts through means forregistering the change in the amplitude of the rhythm which is to beexcited to change the excitation intensity. For this purpose as has beendescribed by way of example above, a computer, an electronic circuit, aprocessor, a programmable electronic circuit (FPGA) or a computerprogram can be used. The range of intensities used in this case islimited at its upper level by safety consideration, this means anavoidance of the triggering of an epileptic response.

During the sensory stimulation described under (1) or (2), the patientis subjected to defined stimuli like, for example Kanisza figures. Thepatient is previously instructed to look for special features in thesestimuli. By feedback over the push button 5, the patient can controlwhether the recognition of the sensory stimulus to which the patient issubjected is improved or enabled by the excitation of the physiologicalrhythm. By at least one and preferably three hiatuses in the reaction ofthe patient, a suitable signal from the control unit 4 is provided tothe means 6 for monitoring the stimulation and thus supplied to theinvestigator. This signal serves to let the investigator know when thepatient is not willing or is not in a position to process the sensorystimulation in accordance with the predetermined requirements as set outabove.

B. Need-Controlled Desynchronization:

The goal of the need-controlled desynchronization is to damp or suppressone or more pathological rhythms which may be too strongly active orexpressed during the processing of sensory stimuli. For this purpose,the stimulus processing which may be destroyed by an excessivelyexpressed neuronal rhythm should be improved or enabled. This result isachieved with the device according to the invention and especially withthe control unit 4 or the above-described means forming part thereof andfunctioning as described in the following.

The sensor 2 registers, for this purpose, the neuronal activity of thebrain area to be damped. The signals measured by the sensor 2 aresupplied to the control unit 4, preferably through the isolatingamplifier. The control unit 4 operates, according to the invention, inaccordance with the following principle:

A rhythmically active neuronal population can be desynchronized with asensory stimulus when the stimulus or excitation on the one hand has thecorrect intensity and duration and, on the other hand, is applied in acritical phase of the corrective oscillation of the neuronal population,the so-called vulnerable phase. Because of the unavoidable variabilityof the frequency of a neuronal population, it is difficult to determineprecisely the vulnerable phase. The problem is solved in accordance withthe invention by the use of complex stimuli. These are comprised of twoqualitatively different stimuli or excitations or pulses:

The first stimulus controls the dynamics of the neuronal population suchthat at the end of this stimulus the dynamic state of the neuronpopulation is known with sufficient precision. For this purpose anentrainment is carried out, that is, an entraining periodic stimulus forexcitation sequence is applied in order to bring the dynamics of theneuron population into step with the stimulus sequence. To this end, thedevice according to the invention, through means for effecting anentrainment, that is a periodic stimulation for the purpose ofcontrolling the rhythm, meaning the phase dynamic, can control theexcitation of the neuronal activity. This can be achieved as has beenindicated in greater detail by example above, with a computer, anelectronic circuit, a processor, a programmable electronic circuit(FPGA) or a computer program.

The second stimulus or excitation follows the first, entrainingstimulation (the stimulation sequence) with a substantially constanttime lag. It encounters the pathologically synchronized, neuronalpopulation in a vulnerable state and gives rise, in this way, to adesynchronization. The second stimulus or excitation pulse is comprisedadvantageously of only a single stimulus or excitation pulse, or a shortperiodic stimulus or pulse sequence, which can be comprised of at leasttwo individual stimuli or pulses and advantageously not more than tenindividual stimuli or excitation pulses. To this end, the device of theinvention is provided with means for desynchronization. Such means, ashas also been indicated by example above, can be a computer, anelectronic circuit, a processor, a programmable electronic circuit(FPGA) or a computer program which is capable of carrying out theprocess steps described below.

The stimulation parameters required for the desynchronization aredetermined in accordance with the invention by the followingstandardization procedure.

1.) Monitoring the quality of the entrainment:

a stimulus for excitation pulse sequence comprised of k preferablyidentical stimuli or excitation pulses are applied one time, preferablyten to one hundred times. In this case, n small values are varied asabove until the entrainment is good enough. The quality of theentrainment is then investigated in the following manner or quantified:

the phase and the amplitude of the neuronal rhythm to be desynchronizedare determined preferably by the Hilbert transformation. An alternativemethod can be the matching in a sliding time window of the signal of theneuronal rhythm with a slowly varied sine function. For this purpose,the device according to the invention is provided with means for testingthe quality of the entrainment. Such means can be, as has been indicatedin an exemplary way above, a computer, an electronic circuit, aprocessor, a programmable electronic circuit (FPGA) or a computerprogram which carries out the described steps.

The effect of the entrainment is that after the entraining stimulation,the neuronal rhythm will always have the same amplitude and above allalways the same phase, independent of the amplitude and the phase at thebeginning of the stimulation. To ensure that this will be the case, thephase or preferably the phase and amplitude are evaluated by means forevaluating phase and amplitude or in a less preferred embodiment of theinvention, exclusively by means for evaluating the phase of the neuronalrhythm in the following manner. For this purpose as has been describedabove by way of example, the described steps can be carried out by acomputer, an electronic circuit, a processor, a programmable electroniccircuit (FPGA) or a computer program.

For the first applied stimulus or excitation pulse sequence, which iscomprised of n individual stimuli or excitation pulses, the means forcarrying out a phase resetting can produce a so called phase-resettingcurve. A phase resetting curve is a phase response curve in which thephase at the end of the stimulation for all m applied excitation orstimuli sequences. A perfect entrainment is obtained when a horizontalphase resetting curves, that is a phase resetting curve which isindependent of the phase at the beginning of the stimulation alwaysassumes the same value as the phase at the end of the stimulation.

The phase resetting curve can be displayed to the researcher for exampleby a display screen forming a means for visualization 6. On the otherhand, the phase resetting curve can be used to evaluate the value of thephase at the end of the stimulation, for example by a simplemathematical operation like determination of the standard deviation ofthe value of the phase, or the quality of the match of a horizontal lineto the phase resetting curve by means for the quantitativecharacterization of the phase resetting curve. Such means, as has alsobeen indicated in an exemplary manner above, can be a computer, anelectronic circuit, a processor, a programmable electronic circuit(FPGA) or a computer program which is designed to carry out thedescribed steps.

Preferably the quality of the entrainment is determined exclusivelyvisually by the investigator through the means for monitoring thestimulation 6. The amplitude is determined in the same way by means ofamplitude resetting curves. The device of the invention can then includemeans for determining the amplitude and for carrying out an amplituderesetting which operates in the following manner. For this purpose theapparatus can include, as was described above in an exemplary manner, acomputer, an electronic circuit, a processor, a programmable electroniccircuit (FPGA) or a computer program which can carry out theabove-described steps. In the amplitude-resetting curves, that isamplitude response curves, the amplitude at the end of the stimulationis plotted against the amplitude at the beginning of the stimulation forall m applied stimulation or excitation sequences. A perfect entrainmentleads to a horizontal amplitude resetting curve, that means, independentfrom the amplitude, at the beginning of the stimulation the amplitude atthe end of the stimulation will assume always the same value. Theamplitude resetting curve is evaluated like the phase resetting curvesquantitatively and/or and preferably only visually.

The number of stimuli or excitation pulses following one another in apulse sequence k is increased until the entrainment is sufficiently goodin terms of amplitude and phase.

In an alternative and preferred embodiment of the invention the qualityof the entrainment is examined in the following manner and quantified.The goal of this alternative procedure is to monitor the quality of theentrainment not only at the end but during the application of the entirestimulus or excitation sequence. This makes the determination of thequality less dependent on fluctuation of the measured neuronal dynamicwhich can be affected either by the measurement process or above all byintrinsic neuronal noise. For this purpose, a stimulus sequencecomprised of k preferably identical stimuli or excitation pulses isapplied one time and preferably ten to one hundred times. K is thenvaried by small values as described above until the entrainment is goodenough. The quality of the entrainment is investigated or quantified inthe following manner:

The signal representing the excited neuronal activity measured by thesensor two is filtered in a band pass filter which completely containsthe frequency peak f_(R) (formula 1) of the resonance frequency but doesnot contain other frequency peaks, the harmonics, subharmonic or otherphysiological or pathological rhythms. Using the Hilbert transformation,the phase φ_(R), that is the phase which is determined from the bandpass filtered signal in this manner. Apart from this, the phase φ_(A) isdetermined, that is the phase of the excitation stimulus sequence orexcitation sequence. This can be achieved in two ways: either a sinefunction can be matched to the stimulus sequence such that the maximumof the signed function will coincide with the point in time at which theindividual stimulus is applied. The phase φ_(A) is then the phase of thematched sine function. Alternatively, the signal which represents thestimulus sequence and thus the sequence of rectangular pulses whichcorrespond to the excitation frequency f_(A) of formula 1 and the bandpass filter is selected. The phase φ_(A) is then the phase determined bythe Hilbert transformation of the band pass filter signal of thestimulus sequence. The band pass used for this purpose must be soselected that it completely encompasses the frequency peak f_(A) in thespectrum of the signal of the excitation sequence but contains no otherfrequency peak. Then the n:m phase difference nφ_(A)−mφ_(b) between theexcitation stimulus sequence and the excited neuronal activity isdetermined. The strength of the entrainment is then preferablydetermined by means of the n:m-entrainment index which is defined asfollows: in the time window used for determining the quality of theentrainment, the distribution of the n:m phase difference is determined.The entropy S of this distribution is then determined according to theformula 2

$\begin{matrix}{S = {- {\sum\limits_{k = 1}^{N}{p_{k}\ln\; p_{k}}}}} & \left( {{Formula}\mspace{14mu} 2} \right)\end{matrix}$whereby, p_(k) is the relative probability that the value of the n:mphase difference will be found in the k the case bin. The number of thebins N is typically determined in accordance with formula 3:N=exp[0.626+0.4 Ln(M−1)  (Formula 3)whereby M is the number of measured values of the n:m phase differenceduring a stimulus sequence.

The n:m entrainment index e_(n,m) is calculated in accordance withformula 4

$\begin{matrix}{e_{n,m} = \frac{S_{\max} - S}{S_{\max}}} & \left( {{Formula}\mspace{14mu} 4} \right)\end{matrix}$whereby S_(max) is the entropy of an equilibrium, that is S_(max)=ln N,whereby the optimum number for determining the distribution in terms ofequidistance partial intervals or bins is given by the formula 3.Through the means of formula 4 a normalization is carried out such that0≦e_(n,m)≦1. e_(n,m)=0 means that no entrainment is present whilee_(n,m)=1 corresponds to a perfect entrainment. The larger the value ofe_(n,m), the better is the entrainment.

Values of e_(n,m) are obtained for each applied stimulus sequence. Fromthat value the mean value

$\begin{matrix}{E_{n,m} = {\frac{1}{l}{\sum\limits_{j = 1}^{l}e_{n,m}^{(j)}}}} & \left( {{Formula}\mspace{14mu} 5} \right)\end{matrix}$is calculated whereby e_(n,m) ^((j)) is the j-the stimulus sequence. Therelationship 0≦E_(n,m)≦1 applies. The number of the k stimuli orexcitation pulses in a stimulus sequence following one another isincreased until the entrainment is sufficiently good, that is untilE_(n,m) sufficiently approaches one.

2.) Determining the Vulnerable Phase:

The vulnerable phase depends upon the intensity and the duration of thesensory stimulation. Advantageously the duration of the sensory stimulusis held constant in the frame work of the standardization procedurewhile the intensity and the vulnerable phase are so varied, as describedbelow, that the desynchronizing effect of the stimulation is maximized.

The determination of the vulnerable phase is carried out with means fordetermining the vulnerable phase. Such means, as has been indicatedabove by way of example previously, can be a computer, an electroniccircuit, a processor, a programmable electronic circuit (FPGA) or acomputer program which can carry out the steps described in thefollowing. In this case the device according to the invention canoperate in two different ways:

A) the time spacing between the last stimulus or excitation pulse of theentraining stimulus or excitation pulse of sequence and thedesynchronizing pulse on the one hand and the intensity of thedesynchronizing stimulus are varied by means for varying the timespacing between the last stimulus of the entrainment and thedesynchronizing stimulus between preferably 0 and 2 period lengths ofthe mean frequency of the frequency band associated with thepathological rhythm in a systematic manner, preferably in smallequidistant steps. The means used for this purpose as has been describedby way of example above, can be a computer, an electronic circuit, aprocessor, a programmable electronic circuit (FPGA) or a computerprogram. This variation in the time spacing is carried outsystematically for different values of the intensity by means of a meansfor varying the intensity. Preferably the intensity is increased insmall equidistant steps and for each value of the intensity, the timespacing is determined as described above between 0 and 2 period lengths.The variation of the time spacing and the intensity is carried outpreferably by the control unit 4. The optimum value for the intensity ofthe sensory stimulus and the time spacing between the last stimulus ofthe entrainment and the desynchronizing stimulus is the value at whichthe strongest desynchronization effect arises, that is the amplitude atwhich the desynchronized rhythm after stimulation is the smallest. Theamplitude is preferably determined by band pass filtration withsubsequent Hilbert transformation.

Alternatively, the amplitude can be determined either by a matching of aslowly varying sine function to the band pass filtered signal of sensortwo in a time window after stimulation or by determining the integratedamplitude over the frequency band of the power spectrum of sensor two ina time window after stimulation.

B) The time spacing is varied under A). Differing from A), the intensityis not increased in equidistant steps but is varied systematically inthe following way: in this case phase resetting curves are used withwhich the effect of the desynchronizing stimulus on the phase dynamicsof the neuronal activity to be desynchronized is investigated. The phaseis advantageously determined by means of band pass filtration and asubsequent Hilbert transformation of the signals measured by the sensortwo. Alternatively to the use of the Hilbert transformation, a slowlyvarying sine function in a sliding time window can be matched to theband pass filter signal of sensor two.

The limits of the pass band can then be the limits of the frequency bandof the pathological neuronal rhythm which is determined at the outset.When reference is made to the phase resetting curves, φ_(e) over φ_(b)are obtained by a means for applying φ_(e), the phase of the neuronalactivity after stimulation, over φ_(b), the phase of the neuronalactivity at the beginning of the stimulation. Such means can be a meansfor investigating the effect of the desynchronizing stimulus on thephase dynamics of the neuronal activity to be desynchronized. Such meanscan as has been indicated above by way of example, be a computer, anelectronic circuit, a processor, a programmable electronic circuit(FPGA) or a computer program.

φ_(e) is thus the phase of the neuronal activity which is determinedeither directly after stimulation or with a constant time delayfollowing stimulation. This time delay should preferably be smaller thanone period length of the neuronal rhythm to be desynchronized or betterstill is equal to 0. Since the period length of the neuronal rhythm isvaried with time, when the reference is made above to period lengths,the period length averaged over time is meant.

φ_(b) is the phase of the neuronal activity which is determined eitherdirectly at the point in time that the stimulation commences or at aconstant time interval prior to the commencement of stimulation. Thetime interval should be, by analogy with the determination of φ_(e), assmall as possible or better still equal to 0. The time interval in thedetermination of φ_(e) or φ_(b) should be as small as possible to ensurethat time dependent variation in the period length will not influencethe quality of the evaluation.

If the selected intensity of the sensory stimulus for desynchronizationis too small, the phase resetting curve will typically have a mean riseof one. If, by contrast, the intensity is too large, the phase resettingcurve will typically have a mean rise of 0.

The optimum intensity value and the optimum value for the lag betweenthe last entrainment pulse and the desynchronizing pulse is determinedwith precision by the location in the phase resetting curve at which thetransition from a mean rise 1 to a mean rise 0 occurs.

This has been shown in FIG. 5. FIG. 5 a through 5 f respectfully showphase resetting curves, whereby in the individual partial figures, theintensity of the sensory stimulus is constant but different from one ofthe partial figures to another and indeed increases from the smallestvalue in FIG. 5 a to the largest value in FIG. 5 f. The optimalstimulation parameter is thus found at the transition from FIG. 5 cthrough 5 e at the location marked by the arrow, (i) the mean value ofthe intensity belonging to FIGS. 5 c and 5 d is optimum for the selectedstimulus duration at which the desynchronization intensity is thestrongest and (ii) the inflection point indicated in FIG. 5 d with thearrow indicates the phase φ_(b) which is optimal for the selectedstimulus duration to which corresponds to the strongest desynchronizingtime interval between the last stimulus of the entrainment and thedesynchronizing stimulus. This time interval can either be given inabsolute time values or, analogously thereto as illustrated in FIG. 5 interms of the phase of the neuronal activity. With the phase resettingcurves it is possible to provide a x-axis equivalent to φ_(b) giving anabsolute time interval between the last excitation of the entrainmentand the desynchronizing excitation. If the experimental data arestrongly affected by noise, the phase resetting curve can be used toprovide a pair of values comprised of intensity and φ_(b) by multiplemeasurements and the mean value of φ_(e) is then used.

The control unit 4 controls the sensory stimulation in two differentways. The need-controlled desynchronization can either be carried outrepetitively or continuously. In both functional methods, an entrainmentis used for the effective desynchronization. The frequency of theentrainment, that is the rate of the entraining sequence of sensorystimuli, is determined in a previous frequency scan. In that frequencyscan it is determined which excitation frequency f_(A) provides amaximum amplitude of the pathological rhythm. If the excitationfrequency f_(A) is identified or a plurality of excitation frequenciesare identified, a desynchronization can be commenced. In the case that aplurality of excitation frequencies are found which lead to maxima inthe amplitude of the pathological rhythm, the desynchronization iscarried out for the one which has the strongest entrainment effect, thatis the strongest excitation of the amplitude.

a) Repetitive Application:

In the repetitive application, the same desynchronizing stimulus orexcitation sequence is repetitively applied. In the pauses between thesedesynchronizing stimulus or excitation sequences no stimulus orexcitation is applied.

The patient is instructed before commencement of the need-controldesynchronization by an investigator or by the device itself. That meansthat the patient is either told by the investigator how he or she shouldrespond to the repetitively applied stimulation or excitation sequencesor the device itself can signal this to the patient by for example byvisual or auditory instruction: the patient hears or reads what he orshe is to do.

For example, the patient must try, upon visual stimulation with therepetitively applied visual stimulus pattern, of certain objects orindividual patterns, for example Kanisza figures to compare them withone another or count them. The investigator controls, using the means 6for monitoring the stimulation, preferably the effect of the stimulationof the brain activity and the information processing by the patientwhich is determined by feedback via the push button 5. The patient mustfor example, each time he recognizes a certain partial pattern, pressthe push button 5. In this manner the investigator is able to determinewhether the applied sensory stimulus improves or enables the damping orsuppression of the pathological rhythm. If the reaction of the patientis missed at least one time, an appropriate signal is provided by thecontrol unit 4 to the means 6 for monitoring the stimulation and thus iscommunicated to the investigator. This signal serves to inform theinvestigator that the patient is not willing or is not capable ofprocessing the sensory stimulus in accordance with the predeterminedconditions.

The control unit 4 controls the application of the sensory stimuli inthe following manner:

An entraining periodic sequence of sensory stimuli or excitation isapplied with the optimum excitation frequency f.sub.A. The sensorystimuli or excitation here used can be identical although they need notnecessarily be identical. Preferably the sensory stimuli used withrespect to the following parameters are identical in order to ensure aneffective entrainment:

(i) They are of the same quality, that is that they deal for examplealways with the same visual pattern.

(ii) They have the same intensity, that is for example the same light orsound amplitude.

(iii) They have the same contrast, that is for example in the case ofvisual stimuli, the same light-dark contrast.

(iv) They have the same duration.

With a constant lag, there is thereafter effected an application of thedesynchronizing stimulus or excitation in a vulnerable phase state ofthe pathological rhythm. The desynchronizing sensory stimulus ispreferably of the same modality, that is, when the entraining stimuliare visual stimuli, the desynchronizing stimulus is also a visualstimulus and for example is without an auditory stimulus.

The desynchronizing stimulus need not however be of the same quality asthe entraining stimuli. Preferably however it is of the same quality,that is it uses for example the same visual pattern. The desynchronizingstimulus differs however preferably from the stimuli of the entrainingstimulus sequence by its duration and/or its intensity and/or itscontrast.

As soon as the desynchronizing stimulus is applied, there is atransitory period in which no stimulus is present. In connection withthis stimulus application, the patient advantageously must signal viathe push button whether he has been able to detect for example specialobjects or visual patterns therein.

Following such a desynchronizing stimulus, there is a pause whoseduration can lie within a statistical distribution in a predeterminedinterval, preferably a uniform distribution. During this pause nostimulus is applied. After this pause, there is a repetition of thecollective of desynchronizing stimuli, comprised of another entrainingstimulus sequence and an individual desynchronizing stimulus.

In the framework of the repetitive application, the control unit 4determines whether the desynchronizing of the pathologically activeneuronal population has been effected, that is whether the damping ofthe pathological rhythm has been strong enough. Should this be the casethe repetition of the stimuli is continued. If the damping of thepathological rhythm is insufficient at least once, restandardizationmust be carried out with the above-described standardization procedure.

FIG. 2 shows an excitation with the resonance frequency which isfollowed by a desynchronization pulse in the vulnerable phase. In thisFigure the x-axis represents the time and the y-axis the intensity ofthe sensory stimulus.

b) Continuous Application:

By contrast with the repetitive application (a) in the continuousapplication, there is a permanent sensory stimulus. Whenever theneuronal activity exceeds a threshold of the above-determined amplitudeof the neuronal activity to be desynchronized, a desynchronization iscarried out. For this purpose an entraining pulse sequence is followedby the application of at least one single stimulus (FIG. 2). In the timebetween the desynchronizations, a continuous sensory stimulationapplies. In this case there are two possibilities:

I) In the time between the desynchronization, stimulation is carried outwith a periodic sequence of sensory stimuli or excitation pulses. Thissequence is comprised of identical individual stimuli which are appliedat a frequency sufficiently different from the resonance frequency thatno resonance arises.

II) In the time between the desynchronization, stimulation is appliedwith a random sequence of sensory stimuli or excitation pulses. Theindividual stimuli of this sequence are comprised of identical visual orauditory patterns in which the following parameters are statisticallyvaried from stimulus or pulse to stimulus or pulse: with visual stimulithe contrast and/or the brightness can be varied. With auditory stimulithe sound volume can be varied. In addition, the pauses between theindividual stimuli and the duration of the individual stimuli can bestatistically varied. In the statistic variation, the correspondingparameters can be varied between the normal physiologically experimentallimit or uniformly.

The purpose of the stimulation described above under I and II is, 1. tocontinuously supply sensory stimuli to patients which can be processedby them so that the patients can continuously have available therequired action, for example, the detection of visual partial images,and 2. to prevent thereby a resonance of the pathological rhythm fromdeveloping.

FIG. 3 a shows a sequence of stimuli by way of example for the means 1for generating the sensory stimuli in the form of a time-spacedapplication of patterns as the sensory stimuli whereby variant I, thatis a periodic stimulation between the desynchronization, is used. InFIG. 3 b the associated activity pattern of the pathologically effectedbrain region has been given. In FIGS. 3 a and 3 b the x-axis is the timeaxis in each. In FIG. 3 a the intensity of the stimulus is plotted alongthe y-axis. In FIG. 3 b the amplitude is a function of time in a slidingtime window for the neuronal activity to be desynchronized has beenplotted.

In FIGS. 3 a and 3 b, the time regions T₁ and T′₁, T₂ and T′₂, T₃ andT′₃, T₄ and T′₄, as well as T₅ and T′₅ are identical. In the timeregions T₁ or T′₁, the amplitude of the pathological rhythms because ofresonance is a maximum. In the time regions T₂ or T′₂, a desynchronizingsensory stimulus is applied in the vulnerable phase to either completelysuppress the pathological activity or at least reduce its intensity.This gives rise to a drop in the amplitude in FIG. 3 b.

As has been described under I above in the time region T.sub.3 aperiodic stimulus sequence is applied whose frequency differssufficiently from the resonance frequency in the time region T₁. Theeffect in the time region T′₃ is that in spite of the sensorystimulation the pathological rhythms will recover only slowly.

In the second case II, in the time region T₃, instead of a periodicstimulus sequence a random or stochastic stimulus sequence is used. Withthis feature the pathological rhythm is suppressed as long as possible.

In FIG. 3 b this phase is characterized by the segment T′₃ in which thecurve of the brain activity to be suppressed reaches its minimum value.As soon as the brain activity in the time region T′₃ again exceeds athreshold value, the need state for desynchronization arises so that inthe next time region T₄ a new desynchronization operation is carriedout. For this purpose in the time region T₄ the same entrainment iseffected as in the time region T₁. Following the entrainment, in thetime region T₅, a desynchronizing stimulus is applied as in the timeregion T₂. For this purpose the sensor 2 registers the increasedactivity of the pathologically affected brain region and reproduces thesignal at the control unit 4 which triggers the next desynchronization.In conjunction with the desynchronization effected in the time regionT₅, a periodic stimulus sequence is applied anew as in the time regionT₃, with a frequency sufficiently different from the resonancefrequency. It corresponds to the above-described case I. Alternativelythereto, also according to the above-described case II, stochastic orrandom stimulus sequences can be used.

The invention comprises a computer program with program code means forcontrolling a device which can carry out at least one of the precedingmethod steps or optional combinations of at least two of the methodsteps given in this description when the program is run on a computer.The invention also encompasses a computer program product with programcode means which is stored on a computer-readable data carrier andpermits the method to be carried out as defined by that computerprogram. This computer-program product can for example be a diskette.The invention also comprises an electronic circuit which is suitable forcarrying out the instructions of the computer program or the computerprogram product.

The invention claimed is:
 1. A method for desynchronizing pathologicallyrhythmic brain activity, the method comprising: generating a periodicsuccession of a plurality of pulses to stimulate neuronal rhythmicactivity in a patient's brain, wherein a frequency at which theplurality of pulses are generated in the periodic succession isincreased from a first limit to a second limit during the periodicsuccession; measuring the neuronal rhythmic activity in response to theperiodic succession of the plurality of pulses; determining at least onefrequency in which a maximum excitation of the neuronal rhythmicactivity is measured in response to the periodic succession of theplurality of pulses; generating an entraining periodic pulse sequenceoperating at the at least one frequency to entrain the phase dynamic ofthe neuronal rhythmic activity; and generating a desynchronization pulsefollowing the entraining periodic pulse sequence to desynchronize theneuronal rhythmic activity, wherein the plurality of pulses, theentraining pulse sequence and the desynchronization pulse are eithervisual or acoustic or tactile.
 2. The method according to claim 1,further comprising generating the periodic succession of the pluralityof pulses at a frequency range of 1 and 100 Hz.
 3. The method accordingto claim 1, further comprising: determining the vulnerable phase of theneuronal rhythmic activity; and generating the desynchronization pulseduring the vulnerable phase of the neuronal rhythmic activity.
 4. Themethod according to claim 1, further comprising repeating the steps ofgenerating the entraining periodic pulse sequence and generating thedesynchronization pulse after a predetermined time interval.
 5. Themethod according to claim 4, further comprising varying the length ofthe time interval between the entraining periodic pulse sequence and thedesynchronization pulse while monitoring the neuronal rhythmic activityto determine an optimal time interval at which the strongestdesynchronization of pathologically rhythmic brain waves of the patientis effected.
 6. The method according to claim 4, further comprising:varying the intensity of each of the repeated desynchronization pulses;and determining an intensity at which the strongest desynchronization ofpathologically rhythmic brain waves is effected.
 7. The method accordingto claim 1, further comprising: generating a continuous sequence ofsensory stimulation after the desynchronization pulse; and repeating thesteps of generating the entraining periodic pulse sequence andgenerating the desynchronization pulse after the continuous sequence ofsensory stimulation.
 8. The method according to claim 7, furthercomprising varying the length of the time interval between theentraining periodic pulse sequence and the desynchronization pulse whilemonitoring the neuronal rhythmic activity to determine an optimal timeinterval at which the strongest desynchronization of pathologicallyrhythmic brain waves of the patient is effected.
 9. The method accordingto claim 7, further comprising: varying the intensity of each of therepeated desynchronization pulses; and determining an intensity at whichthe strongest desynchronization of pathologically rhythmic brain wavesis effected.
 10. The method according to claim 1, wherein the periodicsuccession of the plurality of pulses comprises at least 20 pulses.